Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2008, PMID: 18048362

Signaling by the cysteinyl-leukotriene receptor 2. Involvement in chemokine gene transcription.

Thompson, Charles; Cloutier, Alexandre; Bossé, Ynuk; Poisson, Caroline; Larivée, Pierre; McDonald, Patrick P; Stankova, Jana; Rola-Pleszczynski, Marek

Cysteinyl-leukotrienes are involved in inflammation and act on at least two G-protein-coupled receptors, CysLT1 and CysLT2. However, the role of the CysLT2 receptor as well as its signaling remain poorly understood. Here we show that leukotriene (LT)C(4) induced the production of the chemokine interleukin (IL)-8 in endothelial cells. To further study the signaling cascade involved, HEK293 cells were stably transfected with CysLT2 and used to study the transcriptional regulation of the IL-8 promoter. Stimulation of the cells with increasing concentrations of LTC(4) resulted in a time- and concentration-dependent induction of IL-8 transcription and protein synthesis. Use of IL-8 promoter mutants with substitutions in their NF-kappaB, AP-1, or NF-IL-6 binding elements revealed an almost total requirement for NF-kappaB and AP-1 elements, and a lesser requirement for the NF-IL-6 element. Overexpression of dominant-negative IkappaBalpha prevented the IL-8 transactivation induced by LTC(4). LTC(4) stimulation induced NF-kappaB and AP-1 DNA binding, which involved the formation of a p50/p65 and a c-JUN.c-FOS complex, respectively. Transfection of the cells with a dominant negative (dn) form of PKCepsilon prevented p65 phosphorylation, whereas dnPKCdelta prevented AP-1 binding. Moreover, dnPKCdelta, dnPKCepsilon, and dnPKCzeta prevented LTC(4)-induced IL-8 transcription in response to LTC(4). Our data show for the first time that LTC(4) can act via the CysLT2 receptor to transcriptionally activate chemokine production through induction of NF-kappaB and AP-1 transcription factors. These findings suggest the potential implication of CysLT2 in the inflammatory response through the modulation of chemokine gene transcription.

Diseases/Pathways annotated by Medline MESH: Inflammation
Document information provided by NCBI PubMed

Text Mining Data

IL-8 → IkappaBalpha: " Overexpression of dominant negative IkappaBalpha prevented the IL-8 transactivation induced by LTC ( 4 ) "

AP-1 → c-JUN.c-FOS: " LTC ( 4 ) stimulation induced NF-kappaB and AP-1 DNA binding, which involved the formation of a p50/p65 and a c-JUN.c-FOS complex, respectively "

AP-1 → c-JUN.c-FOS: " LTC ( 4 ) stimulation induced NF-kappaB and AP-1 DNA binding, which involved the formation of a p50/p65 and a c-JUN.c-FOS complex, respectively "

NF-kappaB → c-JUN.c-FOS: " LTC ( 4 ) stimulation induced NF-kappaB and AP-1 DNA binding, which involved the formation of a p50/p65 and a c-JUN.c-FOS complex, respectively "

NF-kappaB → c-JUN.c-FOS: " LTC ( 4 ) stimulation induced NF-kappaB and AP-1 DNA binding, which involved the formation of a p50/p65 and a c-JUN.c-FOS complex, respectively "

Manually curated Databases

No curated data.